The renin-angiotensin system (RAS) plays a critical role in regulation of arterial pressures and sodium homeostasis. Disturbances in this system contribute to the etiology of hypertension, a major risk factor for cardiovascular and renal disease including diabetic nephropathy. As a well established genetic component contributes to the risk of developing hypertension, it is not surprising that polymorphisms in genes encoding the various components of the RAS have been intensely scrutinized both in genetic studies of blood pressure and in studies of conditions in which elevated blood pressure is believed to contribute to disease pathogenesis. Some of the most extensively studied polymorphism(s) of the RAS system are in the gene encoding angiotensin converting enzyme (ACE). This enzyme not only converts angiotensinogen to the biologically active product of the RAS, angiotensin II, but also degrades bradykinin a peptide with vasodilatory activity. While many genetic studies have reported a positive association between polymorphisms in this gene and risk for hypertension and related disorders, an almost equal number have failed to demonstrate such associations. These conflicting results likely reflect the fact that hypertension is a complex genetic disorder resulting from inheritance of a combination of small genetic variations that individually have modest impact. The contribution of a specific variant to hypertension may be difficult to isolate in human populations with varied genetic backgrounds and unique clinical and environmental histories. To address this limitation, we propose to test the hypothesis that polymorphisms in ACE can impact development of hypertension and related diseases using mouse lines which express various alleles of ACE in the absence of the mouse orthologue. Mice homozygous and heterozygous for diseases associated haplotypes will be evaluated under defined environmental conditions for differences in the activity of the RAS, development of hypertension, and development of secondary disease including kidney disease. PUBLIC HEALTH RELEVANCE: Hypertension is a common, chronic disease, and represents an important risk factor for stroke, heart disease and end stage renal disease. With a prevalence of approximately 27% world wide this disease places an enormous economical, health care and social burden on society. There is general consensus that genetic factors contribute to individual susceptibilities to hypertension, and many candidate genes and polymorphisms have been identified through human genetic studies. However, determination of which of these polymorphism(s) is functional and delineation of the mechanism by which the polymorphisms confer risk for disease has been difficult. In this application, using polymorphisms in the ACE gene as an example, we propose a new method for approaching this problem.